Heterocyclic cycloalkanes

ABSTRACT

The invention concerns a heterocyclic cycloalkane of the formula I ##STR1## wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; 
     A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; 
     X is oxy, thio, sulphinyl, sulphonyl or imino; 
     Ar is phenylene which may optionally bear one or two substituents or 
     Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; 
     R 1  is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; 
     and R 2  and R 3  together form a (3-6C)alkylene group which, together with the carbon atom to which R 2  and R 3  are attached, defines a ring having 4 to 7 ring atoms, and which ring may bear one or two substituents; or a pharmaceutically-acceptable salt thereof. 
     The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

This is a division of application Ser. No. 07/793,330, filed Nov. 15,1991, now U.S. Pat. No. 5,217,977 which is a continuation of applicationSer. No. 07/485,492, filed Feb. 27, 1990, now abandoned.

This invention concerns novel heterocyclic cycloalkanes and moreparticularly novel heterocyclic cycloalkanes which are inhibitors of theenzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The inventionalso concerns processes for the manufacture of said heterocycliccycloalkanes and novel pharmaceutical compositions containing saidheterocyclic cycloalkanes. Also included in the invention is the use ofsaid heterocyclic cycloalkanes in the treatment of various inflammatoryand/or allergic diseases in which the direct or indirect products of5-LO catalysed oxidation of arachidonic acid are involved, and theproduction of new medicaments for such use.

As stated above the heterocyclic cycloalkanes described hereinafter areinhibitors of 5-LO, which enzyme is known to be involved in catalysingthe oxidation of arachidonic acid to give rise via a cascade process tothe physiologically active leukotrienes such as leukotriene B₄ (LTB₄)and the peptido-lipid leukotrienes such as leukotriene C₄ (LTC4) andleukotriene D₄ (LTD₄) and various metabolites.

The biosynthetic relationship and physiological properties of theleukotrienes are summarised by G. W. Taylor and S. R. Clarke in Trendsin Pharmacological Sciences, 1986, 7, 100-103. The leukotrienes andtheir metabolites have been implicated in the production and developmentof various inflammatory and allergic diseases such as arthriticdiseases, asthma, allergic rhinitis, atopic dermatitis, psoriasis,cardiovascular and cerebrovascular disorders and inflammatory boweldisease. In addition the leukotrienes are mediators of inflammatorydiseases by virtue of their ability to modulate lymphocyte and leukocytefunction. Other physiologically active metabolites of arachidonic acid,such as the prostaglandins and thromboxanes, arise via the action of theenzyme cyclooxygenase on arachidonic acid.

We have now discovered that certain heterocyclic cycloalkanes areeffective as inhibitors of the enzyme 5-LO and thus of leukotrienebiosyntheses. Thus, such compounds are of value as therapeutic agents inthe treatment of, for example, allergic conditions, psoriasis, asthma,cardiovascular and cerebrovascular disorders, and/or inflammatory andarthritic conditions, mediated alone or in part by one or moreleukotrienes.

According to the invention there is provided a heterocyclic cycloalkaneof the formula I (set out hereinafter) wherein Q is a 6-memberedmonocyclic or 10-membered bicyclic heterocyclic moiety containing one ortwo nitrogen atoms which may optionally bear one, two or threesubstituents selected from halogeno, hydroxy, oxo, carboxy, cyano,amino, (1-4C)alkyl, (1-4C)alkoxy, fluoro-(1-4C)alkyl, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, hydroxy-(1-4C)alkyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy,di-[(1-4C)alkyl]amino-(2-4C)alkoxy and phenyl-(1-4C)alkyl;

wherein A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene orcyclo(3-6C)alkylene;

wherein X is oxy, thio, sulphinyl, sulphonyl or imino;

wherein Ar is phenylene which may optionally bear one or twosubstituents selected from halogeno, hydroxy, amino, nitro, cyano,uerido, carbamoyl, (1-4C)alkyl, (3-4C)alkenyloxy, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl,(1-4C)alkoxycarbonyl, N-[(1-4C)alkyl]carbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoylamino, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy and(1-4C)alkoxycarbonyl-(1-4C)alkoxy; or

Ar is a 6-membered heterocyclene moiety containing up to three nitrogenatoms which may optionally bear one or two substituents selected fromhalogeno, hydroxy, amino, cyano, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino and di-[(1-4C)alkyl]amino;

wherein R¹ is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl,cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R¹ is benzoyl which mayoptionally bear a substituent selected from halogeno, (1-4C)alkyl and(1-4C)alkoxy; and

wherein R² and R³ together form a (3-6C)alkylene group which, togetherwith the carbon atom to which R² and R³ are attached, defines a ringhaving 4 to 7 ring atoms, and which ring may bear one or twosubstituents, which may be the same or different, selected from hydroxy,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl and(1-4C)alkylsulphonyl, or which ring may bear a (1-4C)alkylenedioxysubstituent;

or a pharmaceutically-acceptable salt thereof.

The chemical formulae referred to herein by Roman numerals are set outfor convenience on a separate sheet hereinafter.

In this specification the generic term "alkyl" includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as "propyl" are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as "isopropyl" are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds offormula I defined above may exist in optically active or racemic formsby virtue of one or more substituents containing an asymmetric carbonatom, the invention includes in its definition of active ingredient anysuch optically active or racemic form which possesses the property ofinhibiting 5-LO. The synthesis of optically active forms may be carriedout by standard techniques of organic chemistry yell known in the art,for example by synthesis from optically active starting materials or byresolution of a racemic form. Similarly, inhibitory properties against5-LO may be evaluated using the standard laboratory techniques referredto hereinafter.

It is also to be understood that, insofar as certain of the compounds ofthe formula I as defined above may exhibit the phenomenon oftautomerism, for example a compound of the formula I wherein Q bears anoxo or hydroxy substituent, and as any formula drawings presented hereinmay represent only one of the possible tautomeric forms the inventionincludes in its definition any tautomeric form of a compound of theformula I which possesses the property of inhibiting 5-LO and is not tobe limited merely to any one tautomeric form utilised within theformulae drawings.

Suitable values for the generic terms referred to above include thoseset out below.

A suitable value for Q when it is a 6-membered monocyclic or 10-memberedbicyclic heterocyclic moiety containing one or two nitrogen atoms is,for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl ornaphthyridinyl, or a hydrogenated derivative thereof such as, forexample, 1,2-dihydropyridyl or 1,2-dihydroquinolyl. The heterocyclicmoiety may be attached through any available nitrogen atom and it maybear a substituent on any available position including on any availablenitrogen atom.

When Q is a 10-membered bicyclic heterocyclic moiety containing one ortwo nitrogen atoms it will be appreciated that Q may be attached to Afrom either of the two rings of the bicyclic heterocyclic moiety.

Conveniently Q is, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 5-quinolyl,6-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 6-isoquinolyl,7-isoquinolyl, 3-cinnolyl, 6-cinnolyl, 7-cinnolyl, 2-quinazolinyl,4-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 2-quinoxalinyl,5-quinoxalinyl, 6-quinoxalinyl, 1-phthalazinyl, 6-phthalazinyl,1,5-naphthyridin-2-yl, 1,5-naphthyridin-3-yl, 1,6-naphthyridin-3-yl,1,6-naphthyridin-7-yl, 1,7-naphthyridin-3-yl, 1,7-naphthyridin-6-yl,1,8-naphthyridin-3-yl, 2,6-naphthyridin-6-yl or 2,7-naphthyridin-3-yl.

A suitable value for a halogeno substituent which may be present on Q,Ar or R¹ is, for example, fluoro, chloro, bromo or iodo.

A suitable value for a (1-4C)alkyl substituent which may be present onQ, Ar or R¹ is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl or sec-butyl,

A suitable value for a (1-4C)alkoxy substituent which may be present onQ, Ar or R¹ is, for example, methoxy, ethoxy, propoxy, isopropoxy orbutoxy.

A suitable value for a fluoro-(1-4C)alkyl substituent which may bepresent on Q or Ar, is, for example, fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl orpentafluoroethyl.

A suitable value for A when it is (1-6C)alkylene is, for example,methylene, ethylene, ethylidene, trimethylene, propylidene,tetramethylene or pentamethylene; when it is (3-6C)alkenylene is, forexample, 1-propenylene, 2-methylprop-1-enylene, 3-methylprop-1-enylene,1-butenylene or 2-butenylene; and when it is (3-6C)alkynylene is, forexample, 1-propynylene, 3-methylprop-1-ynylene, 1-butynylene or2-butynylene.

A suitable value for A when it is cyclo(3-6C)alkylene is, for example,cyclopropylidene, 1,2-cyclopropylene, cyclopentylidene,1,2-cyclopentylene, cyclohexylidene or 1,4-cyclohexylene.

A suitable value for Ar when it is phenylene is, for example,1,3-phenylene or 1,4-phenylene.

A suitable value for Ar when it is a 6-membered heterocyclene moietycontaining up to three nitrogen atoms is, for example, pyridylene,pyrimidinylene, pyridazinylene, pyrazinylene or 1,3,5-triazinylene.Conveniently Ar when it is a 6-membered heterocyclene moiety containingup to three nitrogen atoms is, for example, 2,4-, 2,5-, 3,5- or2,6-pyridylene, 2,4-, 2,5- or 4,6-pyrimidinylene, 3,5- or3,6-pyridazinylene or 2,5- or 2,6-pyrazinylene.

Suitable values for substituents which may be present on Q or Arinclude, for example:

    ______________________________________                                        for (1-4C)alkylamino:                                                                         methylamino, ethylamino                                                       propylamino and butylamino;                                   for di-[(1-4C)alkyl]amino:                                                                    dimethylamino, diethylamino and                                               dipropylamino;                                                for amino-(2-4C)alkoxy:                                                                       2-aminoethoxy, 3-aminopropoxy and                                             4-aminobutoxy;                                                for (1-4C)alkylamino-                                                                         2-methylaminoethoxy, 3-                                       (2-4C)alkoxy:   methylaminopropoxy and 2-                                                     ethylaminoethoxy;                                             for di-[(1-4C)alkyl]amino-                                                                    2-dimethylaminoethoxy-3-                                      (2-4C)alkoxy:   dimethylaminopropoxy and                                                      2-diethylaminoethoxy.                                         ______________________________________                                    

Suitable values for substituents which may be present on Q include, forexample:

    ______________________________________                                        for hydroxy-(1-4C)alkyl:                                                                      hydroxymethyl, 1-hydroxyethyl, 2-                                             hydroxyethyl, 2-hydroxypropyl and                                             3-hydroxypropyl;                                              for amino-(1-4C)alkyl:                                                                        aminomethyl, 1-aminoethyl, 2-                                                 aminoethyl, 2-aminopropyl and 3-                                              aminopropyl:                                                  for (1-4C)alkylamino-(1-4C)-                                                                  methylaminomethyl,                                            alkyl:          2-methylaminoethyl,                                                           3-methylaminopropyl,                                                          ethylaminomethyl and                                                          2-ethylaminoethyl;                                            for di-[(1-4C)alkyl]amino-                                                                    dimethylaminomethyl, 2-                                       (1-4C)alkyl:    dimethylaminoethyl,                                                           3-dimethylaminopropyl,                                                        diethylaminomethyl and                                                        2-diethylaminoethyl;                                          for phenyl-(1-4C)alkyl:                                                                       benzyl, phenethyl and                                                         3-phenylpropyl.                                               ______________________________________                                    

Suitable values for substituents which may be present on Ar include, forexample:

    ______________________________________                                        for (3-4C)alkenyloxy:                                                                         allyloxy, methylallyloxy,                                                     but-2-enyloxy and but-3-                                                      enyloxy:                                                      for (1-4C)alkylthio:                                                                          methylthio, ethylthio,                                                        propylthio, isopropylthio and                                                 butylthio;                                                    for (1-4C)alkylsulphinyl:                                                                     methylsulphinyl, ethyl-                                                       sulphinyl, propylsulphinyl,                                                   isopropylsulphinyl and butyl-                                                 sulphinyl;                                                    for (1-4C)alkylsulphonyl:                                                                     methylsulphonyl, ethyl-                                                       sulphonyl, propylsulphonyl,                                                   isopropylsulphonyl and butyl-                                                 sulphonyl;                                                    for (1-4C)alkoxycarbonyl:                                                                     methoxycarbonyl, ethoxy-                                                      carbonyl and tert-butoxy-                                                     carbonyl;                                                     for N-[(1-4C)alkyl]-                                                                          N-methylcarbamoyl, N-ethyl-                                   carbamoyl:      carbamoyl and N-propylcarbamoyl;                              for N,N-di-[(1-4C)alkyl]-                                                                     N,N-dimethylcarbamoyl and N,N-                                carbamoyl:      diethylcarbamoyl;                                             for (2-4C)alkanoylamino:                                                                      acetamido, propionamido and                                                   butyramido;                                                   for cyano-(1-4C)alkoxy:                                                                       cyanomethoxy, 2-cyanoethoxy                                                   and 3-cyanopropoxy;                                           for carbamoyl-(1-4C)alkoxy:                                                                   carbamoylmethoxy, 2-carbamoyl-                                                ethoxy and 3-carbamoylpropoxy;                                for (1-4C)alkoxycarbonyl-                                                                     methoxycarbonylmethoxy, 2-                                    (1-4C)-alkoxy:  methoxycarbonylethoxy, ethoxy-                                                carbonylmethoxy and 2-ethoxy-                                                 carbonylethoxy.                                               ______________________________________                                    

A suitable value for R¹ when it is (1-6C)alkyl is, for example, methyl,ethyl, propyl, butyl, pentyl or hexyl.

A suitable value for R¹ when it is (3-6C)alkenyl is, for example, allyl,2-butenyl or 3-butenyl; and when it is (3-6C)alkynyl is, for example,2-propynyl or 2-butynyl.

A suitable value for R¹ when it is (2-4C)alkanoyl is, for example,acetyl, propionyl or butyryl.

A suitable value for R¹ when it is cyano-(1-4C)alkyl is, for example,cyanomethyl, 2-cyanoethyl or 3-cyanopropyl.

A suitable value for R² and R³ when they together form a (3-6C)alkylenegroup which, together with the carbon atom to which R² and R³ areattached, defines a ring having 4 to 7 ring atoms is, for example,trimethylene, tetramethylene, pentamethylene or hexamethylene. Suitablevalues for the one or two substituents which may be present on said 4-to 7-membered ring include for example:

    ______________________________________                                        for (1-4C)alkyl:                                                                              methyl, ethyl, propyl, isopropyl                                              and butyl;                                                    for (1-4C)alkoxy:                                                                             methoxy, ethoxy, propoxy,                                                     isopropoxy and butoxy;                                        for (1-4C)alkythio:                                                                           methylthio, ethylthio, propylthio,                                            isopropylthio and butylthio;                                  for (1-4C)alkysulphinyl:                                                                      methylsulphinyl, ethylsulphinyl,                                              propylsulphinyl, isopropyl-                                                   sulphinyl and butylsulphinyl;                                 for (1-4C)alkylsulphonyl:                                                                     methylsulphonyl, ethylsulphonyl,                                              propylsulphonyl, isopropyl-                                                   sulphonyl and butylsulphonyl;                                 for (1-4C)alkylenedioxy:                                                                      methylenedioxy and ethylenedioxy.                             ______________________________________                                    

A suitable pharmaceutically-acceptable salt of a heterocycliccycloalkane of the invention which is sufficiently basic is anacid-addition salt with, for example, an inorganic or organic acid, forexample hydrochloric, hydrobromic, sulphuric, phosphoric,trifluoroacetic, citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a heterocyclic cycloalkane of theinvention which is sufficiently acidic (for example a heterocycliccycloalkane of the invention which contains a carboxy group) is analkali metal salt, for example a sodium or potassium salt, an alkalineearth metal salt, for example a calcium or magnesium salt, an ammoniumsalt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention are, for example,heterocyclic cycloalkanes of the formula I wherein:

(a) Q is 2-pyridyl, 3-pyridyl, 3-pyridazinyl, 2-pyrimidinyl or2-pyrazinyl which may optionally bear one substituent selected fromchloro, hydroxy, cyano, methyl, methoxy and trifluoromethyl; and A, X,Ar, R¹, R² and R³ have any of the meanings defined hereinbefore;

(b) Q is 2-pyridyl or 3-pyridyl; A is 1-propenylene or 1-propynylene:and X is oxy; and Ar, R¹, R² and R³ have any of the meanings definedhereinbefore;

(c) Q is 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 3-cinnolyl, 2-quinazolinyl,6-quinazolinyl, 2-quinoxalinyl, 6-quinoxalinyl, 6-phthalazinyl,1,7-naphthyridin-3-yl, 1-7-naphthyridin-6-yl, 1,8-naphthyridin-3-yl or2,7-naphthyridin-3-yl which may optionally bear one or two substituentsselected from fluoro, chloro, hydroxy, oxo, cyano, methyl, methoxy andtrifluoromethyl; and A, X, Ar, R¹, R² and R³ have any of the meaningsdefined hereinbefore;

(d) Q is 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl,2-quinazolinyl, 6-quinazolinyl or 6-quinoxalinyl which may optionallybear one, two or three substituents selected from fluoro, chloro,hydroxy, oxo, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl,2-dimethylaminoethyl and benzyl; and A, X, Ar, R¹, R² and R³ have any ofthe meanings defined hereinbefore;

(e) Q is 1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinolin-6-yl,1,2-dihydro-2-oxoquinolin-7-yl, 3,4-dihydro-4-oxoquinazolin-6-yl,1,2-dihydro-2-oxo-1,7-naphthyridin-3-yl or1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl which may optionally bear one ortwo substituents selected from fluoro, chloro, cyano, methyl, methoxyand trifluoromethyl; and A, X, Ar, R¹, R² and R³ have any of themeanings defined hereinbefore;

(f) Q is 1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinolin-5-yl,1,2-dihydro-2-oxoquinolin-6-yl or 1,2-dihydro-2-oxoquinolin-7-yl whichmay optionally bear one or two substituents selected from fluoro,chloro, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl,2-dimethylaminoethyl and benzyl; and A, X, Ar, R¹, R² and R³ have any ofthe meanings defined hereinbefore;

(g) Q is 1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinolin-5-yl,1,2-dihydro-2-oxoquinolin-6-yl or 1,2-dihydro-2-oxoquinolin-7-yl whichbears a 1-substituent selected from methyl, ethyl, propyl,2-fluoroethyl, 2-dimethylaminoethyl and benzyl, and which may optionallybear a substituent selected from fluoro, chloro and trifluoromethyl; andA, X, Ar, R¹, R² and R³ have any of the meanings defined hereinbefore;

(h) A is methylene, ethylene, trimethylene, 1-propenylene,2-methylprop-1-enylene or 1-propynylene and Q, X, Ar, R¹, R² and R³ haveany of the meanings defined hereinbefore;

(i) A is methylene, 1-propenylene or 1-propynylene; and Q, X, Ar, R¹, R²and R³ have any of the meanings defined hereinbefore;

(j) X is oxy and Q, A, Ar, R¹, R² and R³ have any of the meaningsdefined hereinbefore;

(k) Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear onesubstituent selected from fluoro, chloro, hydroxy, amino, nitro, methyl,methoxy, methylthio, methylsulphinyl, methylsulphonyl, methylamino,dimethylamino, trifluoromethyl, acetamido, cyanomethoxy andcarbamoylmethoxy; and Q, A, X, R¹, R² and R³ have any of the meaningsdefined hereinbefore;

(l) Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear oneor two subsitutents selected from fluoro, chloro, hydroxy, amino ureido,methoxy and trifluoromethyl and Q, A, X, R¹, R² and R³ have any of themeanings defined hereinbefore;

(m) Ar is 2,4-, 2,5-, 3,5- or 2,6-pyridylene or 4,6-pyrimidinylene whichmay optionally bear one substituent selected from chloro methyl andmethoxy; and Q, A, X, R¹, R² and R³ have any of the meanings definedhereinbefore;

(n) Ar is 3,5-pyridylene; and Q, A, X, R¹, R² and R³ have any of themeanings defined hereinbefore;

(o) R¹ is hydrogen, methyl, ethyl, allyl, 2-propynyl or cyanomethyl; andQ, A, X, Ar, R² and R³ have any of the meanings defined hereinbefore;

(p) R¹ is methyl, ethyl, allyl or 2-propynyl; and Q, A, X, Ar, R² and R³have any of the meanings defined hereinbefore;

(q) R² and R³ together form a tetramethylene or pentamethylene groupwhich, together with the carbon atom to which R² and R³ are attached,defines a ring having 5 or 6 ring atoms and which ring may bear asubstituent selected from hydroxy, methyl, methoxy, ethoxy, methylthio,methylsulphinyl, methylsulphonyl and methylenedioxy; and Q, A, X, Ar andR¹ have any of the meanings defined hereinbefore; or

(r) R² and R³ together form a tetramethylene group which, together withthe carbon atom to which R² and R³ are attached, defines a ring having 5ring atoms and which ring may bear a substituent selected from hydroxyand methoxy; and Q, A, X, Ar and R¹ have any of the meanings definedhereinbefore;

or a pharmaceutically-acceptable salt thereof.

A particular compound of the invention comprises a heterocycliccycloalkane of the formula I wherein Q is pyridyl, pyrimidinyl,pyrazinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl which mayoptionally bear one, two or three substituents selected from fluoro,chloro, hydroxy, oxo, methyl, ethyl, propyl, trifluoromethyl,2-fluoromethyl, 2-dimethylaminoethyl and benzyl;

wherein A is methylene, 1-propenylene or 1-propynylene;

wherein X is oxy;

wherein A is 1,3-phenylene or 1,4-phenylene which may optionally bearone or two substituents selected from fluoro, chloro, hydroxy, amino,ureido, methoxy and trifluoromethyl or

Ar is 3,5-pyridylene;

wherein R¹ is methyl, ethyl, allyl or 2-propynyl; and

wherein R² and R³ together form a tetramethylene or pentamethylene groupwhich, together with the carbon atom to which R² and R³ are attached,defines a ring having 5 or 6 ring atoms and which ring may bear asubstituent selected from hydroxy, methyl, methoxy and ethoxy; or apharmaceutically-acceptable salt thereof.

A further particular compound of the invention comprises a heterocycliccycloalkane of the formula I wherein Q is 2-pyridyl, 3-pyridyl,3-pyridazinyl, 2-pyrimidinyl or 2-pyrazinyl which may optionally bearone substituent selected from chloro, hydroxy, cyano, methyl, methoxyand trifluoromethyl, or Q is 2-quinolyl, 3-quinolyl, 6-quinolyl,7-quinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 3-cinnolyl,2-quinazolinyl, 6-quinazolinyl, 2-quinoxalinyl, 6-quinoxalinyl,6-phthalazinyl, 1,7-naphthyridin-3-yl, 1,7-naphthyridin-6-yl,1,8-naphthyridin-3-yl or 2,7-naphthyridin-3-yl which may optionally bearone or two substituents selected from fluoro, chloro, hydroxy, oxo,cyano, methyl, methoxy and trifluoromethyl;

A is methylene, ethylene, trimethylene, 1-propenylene,2-methylprop-1-enylene or 1-propynylene;

X is oxy;

Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear onesubstituent selected from fluoro, chloro, hydroxy, amino, nitro, methyl,methoxy, methylthio, methylsulphinyl, methylsulphonyl, methylamino,dimethylamino, trifluoromethyl, acetamido, cyanomethoxy andcarbamoylmethoxy, or Ar is 2,4-, 2,5-, 3,5- or 2,6-pyridylene or4,6-pyrimidinylene which may optionally bear one substituent selectedfrom chloro, methyl and methoxy;

R¹ is methyl, ethyl, allyl or 2-propynyl; and

R² and R³ together form a tetramethylene or pentamethylene group which,together with the carbon atom to which R² and R³ are attached, defines aring having 5 or 6 ring atoms and which ring may bear a substituentselected from hydroxy, methyl, methoxy, ethoxy, methylthio,methylsulphinyl, methylsulphonyl and methylenedioxy;

or a pharmaceutically-acceptable salt thereof.

A further particular compound of the invention comprises a heterocycliccycloalkane of the formula I wherein Q is 2-pyridyl, 3-pyridyl,3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 6-quinoxalinyl whichmay optionally bear one or two substituents selected from hydroxy, oxo,methyl, ethyl, propyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl;

wherein A is methylene, 1-propenylene or 1-propynylene;

wherein X is oxy;

wherein Ar is 1,3-phenylene or 1,4-phenylene which may optionally bearone to two substituents selected from fluoro, chloro, amino, methoxy andtrifluoromethyl, or Ar is 3,5-pyridylene;

wherein R¹ is methyl, ethyl or allyl; and

wherein R² and R³ together form a tetramethylene group which, togetherwith the carbon atom to which R² and R³ are attached, defines a ringhaving 5 ring atoms and which ring may bear a substituent selected fromhydroxy and methoxy;

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention comprises a heterocycliccycloalkane of the formula I wherein Q is1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinolin-5-yl,1,2-dihydro-2-oxoquinolin-6-yl or 1,2-dihydro-2-oxoquinolin-7-yl whichbears a 1-substituent selected from methyl, ethyl and 2-fluoroethyl;

wherein A is methylene;

wherein X is oxy;

wherein Ar is 1,3-phenylene which may optionally bear one fluorosubstituent;

wherein R¹ is methyl; and

wherein R² and R³ together form a tetramethylene group which, togetherwith the carbon atom to which R² and R³ are attached, defines a ringhaving 5 ring atoms and which ring bears a methoxy substituent;

or a pharmaceutically-acceptable salt thereof.

An especially preferred compound of the invention comprises aheterocyclic cycloalkane of the formula I wherein Q is 2-pyridyl,1,2-dihydro-1-methyl-2-oxoquinolin-3-yl or 6-quinoxalinyl;

A is methylene or 1-propynylene;

Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;

R¹ is methyl; and

R² and R³ together form a tetramethylene group, which, together with thecarbon atom to which R² and R³ are attached, defines a ring having 5ring atoms and which ring bears a 2-methoxy substituent;

or a pharmaceutically-acceptable salt thereof.

Specific especially preferred compounds of the invention include, forexample, the following heterocyclic cycloalkanes of the formula I, orpharmaceutically-acceptable salts thereof:

trans-1,2-dimethoxy-1-[3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]cyclopentane,

(1RS,2SR)-1-[5-fluoro-3-(quinoxalin-6-ylmethoxy)phenyl]-1,2-dimethoxycyclopentaneand

(1RS,2SR)-1-[5-fluoro-3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-1,2-dimethoxycyclopentane.

A compound of the invention comprising a heterocyclic cycloalkane of theformula I, or a pharmaceutically-acceptable salt thereof, may beprepared by any process known to be applicable to the preparation ofstructurally-related compounds. Such procedures are provided as afurther feature of the invention and are illustrated by the followingrepresentative examples in which, unless otherwise stated, Q, A, X, Ar,R¹, R² and R³ have any of the meanings defined hereinbefore.

(a) The alkylation, in the presence of a suitable reagent, of a compoundof the formula II with a compound of the formula Q--A--Z wherein Z is adisplaceable group; provided that, when there is an amino, alkylamino,hydroxy or carboxy group in Q, Ar, R¹, R² or R³, any amino, alkylaminoor carboxy group is protected by a conventional protecting group and anyhydroxy group may be protected by a conventional protecting group oralternatively any hydroxy group need not be protected;

whereafter any undesired protecting group in Q, Ar, R¹, R² or R³ isremoved by conventional means.

A suitable displaceable group Z is, for example, a halogeno,sulphonyloxy or hydroxy group, for example a chloro, bromo, iodo,methanesulphonyloxy or toluene-p-sulphonyloxy group.

A suitable reagent for the alkylation reaction when Z is a halogeno orsulphonyloxy group is, for example, a suitable base, for example, analkali or alkaline earth metal carbonate, hydroxide or hydride, forexample sodium carbonate, potassium carbonate, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride. The alkylationreaction is preferably performed in a suitable inert solvent or diluent,for example N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, andat a temperature in the range, for example, -10° to 150° C.,conveniently at or near ambient temperature.

A suitable reagent for the alkylation reaction when Z is a hydroxy groupis, for example, the reagent obtained when a compound of the formulaQ--A--OH is reacted with a di-(1-4C)alkyl azodicarboxylate in thepresence of a triarylphosphine, for example with diethylazodicarboxylate in the presence of triphenylphosphine. The alkylationreaction is preferably performed in a suitable inert solvent or diluent,for example acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at atemperature in the range, for example, 10° to 80° C., conveniently at ornear ambient temperature.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group for example a (1-4C)alkanoyl group (especiallyacetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl,ethoxycarbonyl or t-butoxycarbonyl), an arylmethoxycarbonyl group(especially benzyloxycarbonyl) or an aroyl group (especially benzoyl).The deprotection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl, alkoxycarbonyl or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a (1-4C)alkyl group (especially methyl orethyl) or an arylmethyl group (especially benzyl). The deprotectionconditions for the above protecting groups necessarily vary with thechoice of protecting group. Thus, for example, an esterifying group suchas an alkyl or arylmethyl group may be removed, for example, byhydrolysis with a suitable base such as an alkali metal hydroxide, forexample lithium or sodium hydroxide. Alternatively an esterifying groupsuch as an arylmethyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example a (1-4C)alkanoyl group (especially acetyl), an aroylgroup (especially benzoyl) or an arylmethyl group (especially benzyl).The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.

The starting materials of the formula II may be obtained by standardprocedures of organic chemistry. The preparation of examples of suchstarting materials is described within the accompanying non-limitingExamples which are provided for the purpose of illustration only. Othernecessary starting materials are obtainable by analogous procedures tothose described or by modification thereto which are within the ordinaryskill of an organic chemist. Thus the starting material of the formulaII may be obtained, for example, by deprotecting a protectedheterocyclic cycloalkane of the formula III wherein R⁴ is a protectinggroup and X, Ar, R¹, R² and R³ have the meanings defined hereinbefore.

A suitable protecting group R⁴ is, for example, an arylmethyl group(especially benzyl), a tri-(1-4C)alkylsilyl group (especiallytrimethylsilyl or t-butyldimethylsilyl), an aryldi-(1-4C)alkylsilylgroup (especially dimethylphenylsilyl), a (1-4C)alkyl group (especiallymethyl), a (1-4C)alkoxymethyl group (especially methoxymethyl) ortetrahydropyranyl group (especially tetrahydropyran-2-yl). Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.Alternatively a trialkylsilyl or an aryldialkylsilyl group such as at-butyldimethylsilyl or a dimethylphenylsilyl group may be removed, forexample, by treatment with a suitable acid such as hydrochloric,sulphuric, phosphoric or trifluoroacetic acid or with an alkali metal orammonium fluoride such as sodium fluoride or, preferably,tetrabutylammonium fluoride. Alternatively an alkyl group may beremoved, for example, by treatment with an alkali metal(1-4C)alkylsulphide such as sodium thioethoxide or, for example, bytreatment with an alkali metal diarylphosphide such as lithiumdiphenylphosphide or, for example, by treatment with a boron oraluminium trihalide such as boron tribromide. Alternatively a(1-4C)alkoxymethyl group or tetrahydropyranyl group may be removed, forexample, by treatment with a suitable acid such as hydrochloric ortrifluoroacetic acid.

The protecting group R⁴ may be, for example, a tri-(1-4C)alkylsilylgroup which can be removed while the protecting group for any amino,alkylamino, carboxy or hydroxy group in Ar, R¹, R² or R³ is retained.

The protected starting material of the formula III may be obtained bystandard procedures of organic chemistry as illustrated in theaccompanying non-limiting Examples. Thus, for example, the protectedstarting material of the formula III, wherein R⁴ has the meaning definedhereinbefore, may be obtained by the alkylation of the tertiary alcoholof the formula IV with an alkylating agent of the formula R¹ --Z,wherein Z is a displaceable group as defined hereinbefore other thanhydroxy, in the presence of a suitable base as defined hereinbefore, andprovided that any amino, alkylamino or hydroxy group in Ar, R² or R³ isprotected by a conventional protecting group.

The tertiary alcohol starting material of the formula IV may be obtainedby the reaction of a compound of the formula R⁴ --X--Ar--Z, wherein R⁴and Ar have the meanings defined hereinbefore and Z is a halogeno groupas defined hereinbefore and provided that any amino, alkylamino orhydroxy group in Ar is protected with a conventional protecting group,with either an organometallic compound of the formula R⁵ --M, wherein R⁵is a (1-6C)alkyl group such as butyl and M is a metallic group, forexample lithium, to give an organometallic compound of the formula R⁴--X--Ar--M, or with a metal such as magnesium to give an organometalliccompound of the formula R⁴ --X--Ar--M--Z; whereafter either of theseorganometallic compounds may be reacted with a ketone of the formula R²--CO--R³, wherein R² and R³ have the meanings defined hereinbefore, andprovided that any hydroxy group in R² and R³ is protected by aconventional protecting group.

(b) The alkylation, in the presence of a suitable base as definedhereinbefore, of a compound of the formula V with a compound of theformula R¹ --Z, wherein R¹ and Z have the meanings defined hereinbefore,provided that, when there is an amino, imino, alkylamino, hydroxy orcarboxy group in Q, X, Ar, R² or R³, any amino, imino, alkylamino,hydroxy or carboxy group is protected by a conventional protectinggroup;

whereafter any undesired protecting group in Q, X, Ar, R² or R³ isremoved by conventional means.

The starting materials of formula V may be obtained by standardprocedures of organic chemistry. The prepartion of examples of suchstarting materials is described within the accompanying non-limitingExamples which are provided for the purpose of. illustration only. Othernecessary starting materials are obtainable by analogous procedures tothose described or by modification thereto which are within the ordinaryskill of an organic chemist. Thus the tertiary alcohol starting materialof the formula V may be obtained, for example, by the alkylation, in thepresence of a suitable base, of a compound of the formula HX--Ar--Z,wherein Ar has the meaning defined hereinbefore and Z is a halogenogroup as defined hereinbefore, with a compound of the formula Q--A--Z,wherein Q, A and Z have the meanings defined hereinbefore, and providedthat any amino, alkylamino, carboxy or hydroxy group in Q or Ar isprotected by a conventional protecting group, to give a compound of theformula Q--A--X--Ar--Z. Alternatively the compound of the formulaQ--A--X--Ar--Z may be obtained, for example, by the alkylation, in thepresence of a suitable base, of a compound of the formula Q--A--XH,wherein Q, A and X have the meanings defined hereinbefore, with acompound of the formula Z--Ar--Z, wherein Z and Ar have the meaningsdefined hereinbefore. The product so obtained may be treated either withan organometallic compound of the formula R⁵ --M, wherein R⁵ is a(1-6C)alkyl group such as butyl and M is a metallic group, for examplelithium, to give an organometallic compound of the formulaQ--A--X--Ar--M, or with a metal such as magnesium to give anorganometallic compound of the formula Q--A--X--Ar--M--Z. Either ofthese organometallic compounds may be reacted with a ketone of theformula R² --CO--R³, provided that any imino or hydroxy group in X, R²or R³ is protected by a conventional protecting group, to give therequired tertiary alcohol starting material of the formula V.

(c) For the production of those compounds of the formula I wherein A isa (3-6C)alkynylene group, the coupling, in the presence of a suitableorganometallic catalyst, of a heterocyclic compound of the formula Q--Z,wherein Q has the meaning defined hereinbefore and Z is a halogeno groupsuch as iodo, with an ethynyl compound of the formula VI, wherein A¹ is(1-4C)alkylene and X, Ar, R¹, R² and R³ have the meanings definedhereinbefore.

A suitable organometallic catalyst is, for example, any agent known inthe art for such a coupling reaction. Thus, for example, a suitablereagent is formed when, for example, bis(triphenylphosphine)palladiumchloride or tetrakis(triphenylphosphine)palladium, and a copper halide,for example cuprous iodide, are mixed. The coupling is generally carriedout in a suitable inert solvent or diluent, for example acetonitrile,1,2-dimethoxyethane, toluene or tetrahydrofuran, at a temperature in therange, for example, 10° to 80° C., conveniently at or near 70° C., andin the presence of a suitable base such as, for example, atri-(1-4C)alkylamine such as triethylamine, or a cyclic amine such aspiperidine.

The ethynyl compound of the formula VI, used as a starting material, maybe obtained, for example, by the alkylation, in the presence of asuitable base, of a compound of the formula II, wherein X, Ar, R¹, R²and R³ have the meanings defined hereinbefore, with an alkylating agentof the formula H--C.tbd.C--A¹ --Z, wherein A¹ has the meaning definedhereinbefore and Z is a halogeno group, and provided that any amino,alkylamino, carboxy or hydroxy group in Ar, R¹, R² or R³ is protected bya conventional protecting group.

(d) For the production of those compounds of the formula I wherein Arbears an alkylsulphinyl or alkylsulphonyl substituent, wherein X is asulphinyl or sulphonyl group, or wherein R² and R³ together form a(3-6C)alkylene group which bears one or two alkylsulphinyl oralkylsulphonyl groups, the oxidation of a compound of the formula Iwherein Ar bears an alkylthio substituent or wherein R² and R³ togetherform a (3-6C)alkylene group which bears one or two alkylthio groups.

A suitable oxidising agent is, for example, any agent known in the artfor the oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or t-butyl methyl ether and at a temperature,for example, at or near ambient temperature, that is in the range 15° to35° C. When a compound carrying a sulphinyl group is required a milderoxidising agent may also be used, for example sodium or potassiummetaperiodate, conveniently in a polar solvent such as acetic acid orethanol. It will be appreciated that when a compound of the formula Icontaining a sulphonyl group is required, it may be obtained byoxidation of the corresponding sulphinyl compound as well as of thecorresponding thio compound.

(e) For the production of those compounds of the formula I wherein Arbears an alkanoylamino substituent, the acylation of a compound of theformula I wherein Ar bears an amino substituent.

A suitable acylating agent is, for example, any agent known in the artfor the acylation of amino to acylamino, for example an acyl halide, forexample a (2-6C)alkanoyl chloride or bromide, in the presence of asuitable base, an alkanoic acid anhydride, for example a (2-6C)alkanoicacid anhydride, or an alkanoic acid mixed anhydride, for example themixed anhydride formed by the reaction of an alkanoic acid and a(1-4C)alkoxycarbonyl halide, for example a (1-4C)alkoxycarbonylchloride, in the presence of a suitable base. In general the reaction iscarried out in a suitable solvent or diluent such as methylene chloride,acetone, tetrahydrofuran or t-butyl methyl ether and at a temperature,for example, at or near ambient temperature, that is in the range 15° to35° C. A suitable base when it is required is, for example, pyridine,4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine,N-methylmorpholine, an alkali metal carbonate, for example potassiumcarbonate, or an alkali metal carboxylate, for example sodium acetate.

(f) For the production of those compounds of the formula I wherein R¹ isalkanoyl or benzoyl optionally bearing a substituent as definedhereinbefore, the acylation of a compound of the formula I wherein R¹ ishydrogen. For the production of those compounds of the formula I whereinR¹ is alkanoyl the acylation reaction may be carried out using, forexample, a suitable acylating agent as defined hereinbefore. For theproduction of those compounds of the formula I wherein R¹ is benzoyloptionally bearing a substituent the acylation may be carried out using,for example, a benzoyl halide, for example a benzoyl chloride orbromide, in the presence of a suitable base as defined hereinbefore.

(g) For the production of those compounds of the formula I wherein A isalkenylene, R¹ is alkenyl, the reduction of the corresponding compoundwherein A is alkynylene or R¹ is alkynyl.

In general conditions which are standard in the art for the reduction ofan alkynyl or alkynylene group are used. Thus, for example, thereduction may be carried out by the hydrogenation of a solution of thealkynyl or alkynylene compound in an inert solvent or diluent in thepresence of a suitable metal catalyst. A suitable inert solvent is, forexample, an alcohol, for example methanol or ethanol, or an ether, forexample tetrahydrofuran or t-butyl methyl ether. A suitable metalcatalyst is, for example, palladium or platinum on an inert support, forexample charcoal or barium sulphate. Preferably a palladium-on-bariumsulphate catalyst is used to substantially prevent over-reduction of thealkynyl or alkynylene group to an alkyl or alkylene group respectively.The reaction is generally carried out at a temperature at or nearambient temperature, that is in the range 15° to 35° C.

Alternatively the reduction may be carried out by treating a solution ofthe alkynyl or alkynylene compound in an inert solvent or diluent with asuitable mixture such as a 1:1 mixture of an organometallic hydride, forexample a di-(1-6C)alkylaluminium hydride such as diisobutylaluminiumhydride, and an alkyl metal, for example a (1-6C)alkyl lithium such asmethyl lithium. A suitable inert solvent or diluent is, for example,tetrahydrofuran, diethyl ether or t-butyl methyl ether and, in general,the reaction is carried out at a temperature, for example, in the range-25° C. to ambient temperature (especially -10° to 10° C.).

(h) For the production of those compounds of the formula I wherein Qbears an alkyl or substituted alkyl substitutent on an availablenitrogen atom, or wherein Ar bears an alkoxy or substituted alkoxysubstituent, the alkylation of a compound of the formula I wherein Qbears a hydrogen atom on said available nitrogen atom, or wherein Arbears a hydroxy substituent.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of an available nitrogen atom, or of hydroxy toalkoxy or substituted alkoxy, for example an alkyl or substituted alkylhalide, for example a (1-6C)alkyl chloride, bromide or iodide or asubstituted (1-4C)alkyl chloride, bromide or iodide, in the presence ofa suitable base. A suitable base for the alkylation reaction is, forexample, an alkali or alkaline earth metal carbonate, hydroxide orhydride, for example sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, sodium hydride or potassium hydride. Thealkylation reaction is preferably performed in a suitable inert solventor diluent, for example N,N-dimethylformamide, dimethylsulphoxide,acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature inthe range, for example, 10° to 150° C., conveniently at or near ambienttemperature.

(i) For the production of those compounds of the formula wherein or Arbears an amino substituent, the reduction of a compound of the formula Iwherein Q or Ar bears a nitro substituent.

A suitable reducing agent is, for example, any agent known in the artfor the reduction of a nitro group to an amino group. Thus, for example,the reduction may be carried out by the hydrogenation of a solution ofthe nitro compound in an inert solvent or diluent in the presence of asuitable metal catalyst, for example finely divided platinum metal(obtained by the reduction of platinum oxide in situ). A suitable inertsolvent or diluent is, for example, an alcohol, for example methanol,ethanol or isopropanol, or an ether, for example tetrahydrofuran.

A further suitable reducing agent is, for example an activated metalsuch as activated iron (produced by washing iron powder with a dilutesolution of an acid such as hydrochloric acid). Thus, for example, thereduction may be carried out by heating a mixture of the nitro compoundand the activated metal in a suitable solvent or diluent such as amixture of water an alcohol, for example, methanol or ethanol, to atemperature in the range, for example, 50° to 150° C., conveniently ator near 70° C.

When a pharmaceutically-acceptable salt of a novel compound of theformula I is required, it may be obtained, for example, by reaction ofsaid compound with a suitable acid or base using a conventionalprocedure. When an optically active form of a compound of the formula Iis required, it may be obtained by carrying out one of the aforesaidprocedures using an optically active starting material, or by resolutionof a racemic form of said compound using a conventional procedure.

Many of the intermediates defined herein are novel, for example those ofthe formula V, and these are provided as a further feature of theinvention.

As stated previously, the heterocyclic cycloalkanes of the formula I areinhibitors of the enzyme 5-LO. The effects of this inhibition may bedemonstrated using one or more of the standard procedures set out below:

a) An in vitro spectrophotometric enzyme assay system, which assessesthe inhibitory properties of a test compound in a cell free system using5-LO isolated from guinea pig neutrophils and as described by D. Aharonyand R. L. Stein (J. Biol. Chem., 1986, 261(25), 11512-11519). This testprovides a measure of the intrinsic inhibitory properties againstsoluble 5-LO in an extracellular environment.

b) An in vitro assay system involving incubating a test compound withheparinised human blood, prior to challenge with the calcium ionophoreA23187 and then indirectly measuring the inhibitory effects on 5-LO byassaying the amount of LTB₄ using the specific radioimmunoassaydescribed by Carey and Forder (F. Carey and R. A. Forder, Brit. J.Pharmacol. 1985, 84, 34P) which involves the use of a protein-LTB₄conjugate produced using the procedure of Young et alia (Prostaglandins,1983, 26(4), 605-613). The effects of a test compound on the enzymecyclooxygenase (which is involved in the alternative metabolic pathwayfor arachidonic acid and gives rise to prostaglandins, thromboxanes andrelated metabolites) may be measured at the same time using the specificradioimmunoassay for thromboxane B₂ (TxB₂) described by Carey and Forder(see above). This test provides an indication of the effects of a testcompound against 5-LO and also cyclooxygenase in the presence of bloodcells and proteins. It permits the selectivity of the inhibitory effecton 5-LO or cyclooxygenase to be assessed.

c) An ex vivo assay system, which is a variation of test b) above,involving administration of a test compound (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to carboxymethylcellulose), bloodcollection, heparinisation, challenge with A23187 and radioimmunoassayof LTB₄ and TxB₂. This test provides an indication of thebioavailability of a test compound as an inhibitor of 5-LO orcyclooxygenase.

d) An in vitro assay system involving the measurement of the inhibitoryproperties of a test compound against the liberation of LTC₄ and PGE₂induced by zymosan on mouse resident peritoneal macrophages, using theprocedure of Humes (J. L. Humes et alia, Biochem. Pharmacol., 1983, 32,2319-2322) and conventional radioimmunoassay systems to measure LTC₄ andPGE₂. This test provides an indication of inhibitory effects against5-LO and cyclooxygenase in a non-proteinaceous system.

e) An in vivo system involving the measurement of the effects of a testcompound in inhibiting the inflammatory response to arachidonic acid inthe rabbit skin model developed by D. Aked et alia (Brit. J. Pharmacol.,1986, 89, 431-438). This test provides an in vivo model for 5-LOinhibitors administered topically or orally.

f) An in vivo system involving measuring the effects of a test compoundadministered orally or intravenously on a leukotriene dependentbronchoconstriction induced by an antigen challenge in guinea pigspre-dosed with an antihistamine (mepyramine), a beta-adrenergic blockingagent (propranolol) and a cyclooxygenase inhibitor (indomethacin), usingthe procedure of W. H. Anderson et alia (British J. Pharmacology, 1983,78(1), 67-574). This test provides a further in vivo test for detecting5-LO inhibitors.

Although the pharmacological properties of the compounds of the formulaI vary with structural changes as expected, in general compounds of theformula I possess 5-LO inhibitory effects at the followingconcentrations or doses in one or more of the above tests a)-f):

Test a): IC₅₀ in the range, for example, 0.01-30 micromolar;

Test b): IC₅₀ (LTB₄) in the range, for example, 0.01-40 micromolar, IC₅₀(TxB₂) in the range, for example, 40-200 micromolar;

Test c): oral ED₅₀ (LTB₄) in the range, for example, 1-200 mg/kg;

Test d): IC₅₀ (LTC₄) in the range, for example, 0.001-1 micromolar, IC₅₀(PGE₂) in the range, for example, 20-1000 micromolar;

Test e): inhibition of inflammation in the range, for example, 0.3-100micrograms intradermally;

Test f): ED₅₀ in the range, for example, 0.5-10 mg/kg i.v.

No overt toxicity or other untoward effects are present in tests c), e)and/or f) when compounds of the formula I are administered at severalmultiples of their minimum inhibitory dose or concentration.

Thus, by way of example, the compoundtrans-1,2-dimethoxy-1-[3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]cyclopentanehas an IC₅₀ of 8.0 μM against LTB₄ and of >40 micromolar against TxB₂ intest b), and an oral ED₅₀ of <100 mg/kg against LTB₄ in test c). Ingeneral those compounds of the formula I which are particularlypreferred have an IC₅₀ of <1 micromolar against LTB₄ and of >40micromolar against TxB₂ in test b), and an oral ED₅₀ of <100 mg/kgagainst LTB₄ in test c).

These compounds are examples of heterocyclic cycloalkanes of theinvention which show selective inhibitory properties for 5-LO as opposedto cyclooxygenase, which selective properties are expected to impartimproved therapeutic properties, for example, a reduction in or freedomfrom the gastrointestinal side-effects frequently associated withcyclooxygenase inhibitors such as indomethacin.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a heterocyclic cycloalkane ofthe formula I, or a pharmaceutically-acceptable salt thereof, inassociation with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powderor a liquid aerosol; for sub-lingual or buccal use, for example a tabletor capsule; or for parenteral use (including intravenous, subcutaneous,intramuscular, intravascular or infusion), for example a sterile aqueousor oily solution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is a heterocyclic cycloalkane ofthe formula I or a pharmaceutically-acceptable salt thereof) that iscombined with one or more excipients to produce a single dosage formwill necessarily vary depending upon the host treated and the particularroute of administration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient.

According to further feature of the invention there is provided aheterocyclic cycloalkane of the formula I, or apharmaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

The invention also includes a method of treating a disease or medicalcondition mediated alone or in part by one or more leukotrienes whichcomprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as defined above.The invention also provides the use of such an active ingredient in theproduction of a new medicament for use in a leukotriene mediated diseaseor medical condition.

The size of the dose for therapeutic or prophylactic purposes of acycloalkane of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, heterocyclic cycloalkanes of the formula Iare useful in treating those allergic and inflammatory conditions whichare due alone or in part to the effects of the metabolites ofarachidonic acid arising by the linear (5-LO catalysed) pathway and inparticular the leukotrienes, the production of which is mediated by5-LO. As previously mentioned, such conditions include, for example,asthmatic conditions, allergic reactions, allergic rhinitis, allergicshock, psoriasis, atopic dermatitis, cardiovascular and cerebrovasculardisorders of an inflammatory nature, arthritic and inflammatory jointdisease, and inflammatory bowel diseases.

In using a compound of the formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used.

Although the compounds of the formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the enzyme 5-LO.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

By virtue of their effects on leukotriene production, the compounds ofthe formula I have certain cytoprotective effects, for example they areuseful in reducing or suppressing certain of the adversegastrointestinal effects of the cyclooxygenase inhibitory non-steroidalanti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylicacid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore,co-administration of a 5-LO inhibitor of the formula I with a NSAIA canresult in a reduction in the quantity of the latter agent needed toproduce a therapeutic effect, thereby reducing the likelihood of adverseside-effects. According to a further feature of the invention there isprovided a pharmaceutical composition which comprises a heterocycliccycloalkane of the formula I, or a pharmaceutically-acceptable saltthereof as defined hereinbefore, in conjunction or admixture with acyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such asmentioned above), and a pharmaceutically-acceptable diluent or carrier.

The cytoprotective effects of the compounds of the formula I may bedemonstrated, for example in a standard laboratory model which assessesprotection against indomethacin-induced or ethanol-induced ulceration inthe gastrointestinal tract of rats.

The compositions of the invention may in addition contain one or moretherapeutic or prophylactic agents known to be of value for the diseaseunder treatment. Thus, for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionate), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

The compounds of the formula I may also be used in combination withleukotriene antagonists such as those disclosed in European PatentSpecifications Nos. 179619, 199543, 220066, 227241, 242167, 290145,337765, 337766 and 337767, which are incorporated herein by way ofreference.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporations in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at room temperature, that is in therange 18°-20° and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) obtained from E. Meck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end-products of the formula I have satisfactory microanalysesand their structures were confirmed by NMR and mass spectral techniques;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;and

(vii) melting points are uncorrected and were determined using a MerrierSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the formula I were determined afterrecrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture.

EXAMPLE 1

A mixture of 3-bromomethyl-1,2-dihydroquinolin-2-one (0.512 g, Chem.Pharm. Bull., 1985, 33, 3775),1-(3-hydroxyphenyl)-trans-1,2-dimethoxycyclopentane (0.37 g), potassiumcarbonate (0.274 g) and dimethylformamide (3 ml) was stirred at ambienttemperature for 15 hours. The mixture was partitioned between methylenechloride and water. The organic layer was washed with a saturatedaqueous sodium chloride solution, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 1:1 v/v mixture oftoluene and ethyl acetate as eluent. There was thus obtained1-[3-(1,2-dihydro-2-oxoquinolin-3-ylmethoxy)phenyl]-trans-1,2-dimethoxycyclopentane(0.53 g, 86%), m.p. 100°-102° C.

The 1-(3-hydroxyphenyl)-trans-1,2-dimethoxycyclopentane, used as astarting material, was obtained as follows:

3-Methoxymethoxyphenyl bromide was prepared by the reaction of3-bromophenol and dimethoxymethane using the general procedure describedin Synthesis, 1976, 244. A Grignard reagent was prepared by heating amixture of 3-methoxymethoxyphenyl bromide (5 g), magnesium (0.55 g) andtetrahydrofuran (20 ml) to 30° C. for 2 hours. The reagent was cooled toambient temperature and a solution of 2-methoxycyclopentanone (2.5 g;Bull. Soc. Chim. France, 1973, 1417) in tetrahydrofuran (8 ml) was addeddropwise. The mixture was stirred at ambient temperature for 15 hoursand evaporated. The residue was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using initially methylene chloride andthen increasingly polar mixtures of methylene chloride and diethylether, up to a 1:1 v/v mixture, as eluent. There was thus obtained1-hydroxy-2-methoxy-1-(3-methoxymethoxyphenyl)cyclopentane (3.11 g,56%), as an oil.

A mixture of the product so obtained, sodium hydride (55% w/w dispersionin mineral oil, 1 g) and dimethylformamide (70 ml) was stirred atambient temperature for 15 minutes. Methyl iodide (2 ml) and1,4,7,10,13-pentaoxacyclopentadecane (hereinafter 15-crown-5, 0.1 g)were added and the mixture was stirred at ambient temperature for 15hours. The mixture was evaporated and the residue was partitionedbetween methylene chloride and water. The organic layer was separated,washed with water, dried (MgSO₄) and evaporated. There was thus obtaineda mixture of diastereoisomers of1,2-dimethoxy-1-(3-methoxymethoxyphenyl)cyclopentane from which the lesspolar isomer, trans-1,2-dimethoxy-1-(3-methoxymethoxyphenyl)cyclopentane(0.9 g, 47%) was obtained by column chromatography using a 49:1 v/vmixture of methylene chloride and diethyl ether as eluent.

A mixture of the trans-isomer so obtained (0.515 g), concentratedhydrochloric acid (0.1 ml), isopropanol (1 ml) and tetrahydrofuran (5ml) was stirred at ambient temperature for 15 hours. The mixture wasevaporated and the residue was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 9:1 v/v mixture of methylenechloride and diethyl ether as eluent. There was thus obtained1-(3-hydroxyphenyl)-trans-1,2-dimethoxycyclopentane (0.24 g, 57%), m.p.73°-74° C.

EXAMPLE 2

The procedure described in Example 1 was repeated except that3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was used in place of3-bromomethyl-1,2-dihydroquinolin-2-one. There was thus obtainedtrans-1,2-dimethoxy-1-[3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]cyclopentaneas an oil in 72% yield.

NMR Spectrum: (CDCl₃, delta values) 1.56-2.26(m, 6H), 2.96(s, 3H),2.97(s, 3H), 3.6(d, 1H), 4.94(s, 2H), 6.99-7.64(m, 7H), 8.59(d, 1H).

3-(2-Pyridyl)prop-2-yn-1-yl bromide hydrobromide used as a startingmaterial was obtained as follows:

2-Propynyl alcohol (35 ml) was added dropwise to a stirred mixture of2-bromopyridine (13.7 g), bis(triphenylphosphine)palladium chloride(1.54 g), triethylamine (21 ml), cuprous iodide (1.5 g) and acetonitrile(150 ml) and the mixture was stirred at ambient temperature for 30minutes and then heated to 60° C. for 2 hours. The mixture was cooled toambient temperature, poured into water (200 ml) and neutralised byadding dilute aqueous hydrochloric acid. The mixture was extracted withmethylene chloride (2×500 ml) and the combined extracts were washed withwater (500 ml), dried (MgSO₄) and evaporated. The residue was purifiedby column chromatography eluting with a 1:1 v/v mixture of methylenechloride and ethyl acetate to give 3-(2-pyridyl)prop-2-yn-1-yl alcohol(14 g, 70%), m.p. 78°-80° C. (recrystallised from a mixture of hexaneand ethyl acetate).

A solution of bromine (3.1 ml) in methylene chloride (3 ml) was added toa mixture of triphenylphosphine (10.1 g) and methylene chloride (72 ml)which had been cooled to -8° C. in a salted ice-bath. A solution of thealcohol (4.8 g) obtained immediately above in methylene chloride (36 ml)was added and the mixture was stirred for 10 minutes and cooled toapproximately -10° C. The mixture was filtered to give3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide (5.8 g., 58%), m.p.112°-114° C., which was used without further purification.

EXAMPLE 3

Using the procedure described in Example 1, 3-(2-pyridyl)prop-2-yn-1-ylbromide hydrobromide was reacted with(1RS,2SR)-1-(5-fluoro-3-hydroxyphenyl)-1,2-dimethoxycyclopentane to give(1RS,2SR)-1-[5-fluoro-3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]-1,2-dimethoxycyclopentanein 83% yield, as an oil.

NMR Spectrum (CDCl₃, delta values) 1.6°-2.25(m, 6H), 2.94(s, 3H),2.97(s, 3H), 3.55(m, 1H), 5.21(s, 2H), 6.55-8.0(m, 10H).

The (1RS,2SR)-1-(5-fluoro-3-hydroxyphenyl)-1,2-dimethoxycyclopentane,used as a starting material, was obtained as follows:

Benzyl alcohol (1.0 g) was added to a suspension of sodium hydride (60%w/w dispersion in mineral oil, 0.48 g) in dimethylacetamide (15 ml) andthe mixture was stirred at ambient temperature for 5 minutes. Themixture was cooled in an ice-bath and 3,5-difluorobromobenzene (1.15 ml)was added. The mixture was stirred at ambient temperature for 30 minutesand then partitioned between diethyl ether and water. The organic phasewas washed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using methylene chloride as eluent.There was thus obtained 3-benzyloxy-5-fluorobromobenzene (2.34 g, 83%),as an oil.

After repetition of the above reaction, a solution of2-methoxycyclopentanone (12.5 g) in tetrahydrofuran (10 ml) was added toa solution of 3-benzyloxy-5-fluorophenylmagnesium bromide [prepared byheating a mixture of 3-benzyloxy-5-fluorobromobenzene (31 g), magnesiumpowder (2.65 g) and tetrahydrofuran (20 ml) to 40° C. for 2 hours] andthe mixture was stirred at ambient temperature for 2 hours. The mixturewas evaporated and the residue was partitioned between diethyl ether andrarer, The organic layer was washed with water, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a9:1 v/v mixture of methylene chloride and diethyl ether as eluent. Therewas thus obtained, as a mixture of diastereoisomers,1-(3-benzyloxy-5-fluorophenyl)-2-methoxycyclopentanol (21.7 g, 62%), asan oil.

Using the procedure described in the second paragraph of the portion ofExample 1 which is concerned with the preparation of starting materials,a portion (18.2 g) of the product so obtained was reacted with methyliodide to give, as a mixture of diastereoisomers,1-(3-benzyloxy-5-fluorophenyl)-1,2-dimethoxycyclopentane. Thediastereoisomers were separated by column chromatography using a 49:1v/v mixture of methylene chloride and diethyl ether as eluent. There wasthus obtained in pure form the diastereoisomer wherein the methoxygroups are in trans-relationship i.e.(1RS,2SR)-1-(3-benzyloxy-5-fluorophenyl)-1,2-dimethoxycyclopentane (12.7g, 67%).

A mixture of a portion (6.5 g) of the compound so obtained, 10%palladium-on-charcoal catalyst (0.65 g) and ethanol (100 ml) was stirredunder an atmosphere of hydrogen for 3 hours. The mixture was filteredand the filtrate was evaporated. There was thus obtained the requiredstarting material (4.58 g, 95%), m.p. 94°-95° C.

EXAMPLE 4

Using the procedure described in Example 1, the appropriate alkylbromide was reacted with the appropriate cyclopentanol to give thecompounds described in the following table:

                  TABLE I                                                         ______________________________________                                         ##STR2##                                                                     Ex. 4                                                                         Compd.                          Yield m.p.                                    No.    Q              Ar        (%)   (°C.)                            ______________________________________                                        1.sup.a                                                                              6-quinoxalinyl 5-fluoro- 75    60-61                                                         1,3-                                                                          phenylene                                               2.sup.b                                                                              1,2-dihydro-1-methyl-                                                                        5-fluoro- 57    85                                             2-oxoquinolin-6-yl                                                                           1,3-                                                                          phenylene                                               3.sup.c                                                                              1,2-dihydro-1-methyl-                                                                        5-fluoro- 75    137-139                                        2-oxoquinolin-5-yl                                                                           1,3-                                                                          phenylene                                               4.sup.d                                                                              1,2-dihydro-1-methyl-                                                                        5-fluoro- 76    116-118                                        2-oxoquinolin-7-yl                                                                           1,3-                                                                          phenylene                                               5.sup.e                                                                              1,2-dihydro-1-(2-                                                                            5-fluoro- 61    109-112                                        fluoroethyl)-2-                                                                              1,3-                                                           oxoquinolin-6-yl                                                                             phenylene                                               6.sup.f                                                                              1,2-dihydro-1-ethyl-                                                                         5-fluoro- 59    115-116                                        2-oxoquinolin-6-yl                                                                           1,3-                                                                          phenylene                                               ______________________________________                                    

Notes

a. 6-Bromomethylquinoxaline, used as the alkylating agent, is describedin J. Het. Chem., 1974, 11, 595.

b. The 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as astarting material, was obtained as follows:

A mixture of 1,2-dihydro-1,6-dimethylquinolin-2-one (4.4 g; Helv. Chim.Acta, 1970, 53, 1903), N-bromosuccinimide (4.53 g),azobisisobutyronitrile (0.01 g) and carbon tetrachloride (75 ml) washeated to reflux for 3 hours and illuminated with the light from a 275watt lamp. The mixture was evaporated and the residue was partitionedbetween ethyl acetate and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 2:1 v/v mixture of toluene and ethyl acetate aseluent. There was thus obtained the required starting material (4.8 g,75%), as a solid, m.p 108°-108° C.

NMR Spectrum (CDCl₃, delta values) 3.7(s, 3H), 4.57(s, 2H), 6.7-7.5(d,1H), 7.25-7.65(m, 4H).

c. The 5-bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as astarting material, was obtained as follows:

1,2-Dihydro-5-methylquinolin-2-one (1.59 g; Synthesis, 1975, 739) wasadded to a stirred suspension of sodium hydride (55% w/w dispersion inmineral oil, 0.264 g) in dimethylformamide (40 ml) and the mixture washeated to 50° C. for 45 minutes. The mixture was cooled to 0° C. andmethyl iodide (0.93 ml) was added dropwise. The mixture was stirred atambient temperature for 16 hours. The mixture was evaporated and theresidue was partitioned between ethyl acetate and water. The organicphase was washed with a saturated aqueous sodium chloride solution,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 19:1 v/v mixture of methylene chloride andmethanol as eluent. There was thus obtained1,2-dihydro-1,5-dimethylquinolin-2-one (1.5 g, 87%), m.p. 107°-108° C.

A mixture of a portion (1.21 g) of the product so obtained,N-bromosuccinimide (1.37 g), benzoyl peroxide (0.035 g) and carbontetrachloride (25 ml) was heated to reflux for 40 minutes and irradiatedwith the light from a 275 watt lamp. The mixture was evaporated and theresidue was partitioned between ethyl acetate and water. The organicphase was washed with a saturated aqueous sodium chloride solution,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using in turn methylene chloride and then a 4:1 v/vmixture of toluene and ethyl acetate as eluent. There was thus obtainedthe required starting material (1.09 g, 59%), m.p. 169° C.

d. The 7-bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as astarting material, was obtained using the following procedure:

1,2-Dihydro-7-methylquinolin-2-one (Synthesis, 1975, 739) was reactedwith methyl iodide using the procedure described in Note c. immediatelyabove. There was thus obtained 1,2-dihydro-1,7-dimethylquinolin-2-one in79% yield, m.p. 111°-112° C.

The product so obtained was brominated using the procedure described inNote c. immediately above to give the required starting material in 57%yield, m.p. 170° C.

e. The 6-bromomethyl-1,2-dihydro-1-(2-fluoroethyl)quinolin-2-one, usedas the alkylating agent, was obtained from1,2-dihydro-6-methylquinolin-2-one using the procedures described inNote c. immediately above, except that 2-fluoroethyl bromide was used inplace of methyl iodide. There was thus obtained the required startingmaterial in 48% yield, as a solid.

NMR Spectrum (CDCl₃, delta values) 4.56(s, 2H), 4.5-4.9(m, 4H), 6.72(d,1H), 7.3-7.8(m, 4H)

f. The 6-bromomethyl-1,2-dihydro-1-ethylquinolin-2-one, used as astarting material, was obtained from 1,2-dihydro-6-methylquinolin-2-oneusing the procedures described in Note c. immediately above except thatethyl iodide was used in place of methyl iodide. There was thus obtainedthe required starting material in 21% yield, as an oil.

NMR Spectrum (CDCl₃, delta values) 1.38(t, 3H), 4.35(q, 2H), 4.57(s,2H),6.72(d, 1H), 7.63(d, 1H), 7.1-7.6(m, 3H).

EXAMPLE 5

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically-acceptablesalt salt thereof (hereafter compound X), for therapeutic orprophylactic use in humans:

    ______________________________________                                        (a)  Tablet I              mg/tablet                                               Compound X            100                                                     Lactose Ph.Eur        182.75                                                  Croscarmellose sodium 12.0                                                    Maize starch paste (5% w/v paste)                                                                   2.25                                                    Magnesium stearate    3.0                                                (b)  Tablet II             mg/tablet                                               Compound X            50                                                      Lactose Ph.Eur        223.75                                                  Croscarmellose sodium 6.0                                                     Maize starch          15.0                                                    Polyvinylpyrrolidone (5% w/v paste)                                                                 2.25                                                    Magnesium stearate    3.0                                                (c)  Tablet III            mg/tablet                                               Compound X            1.0                                                     Lactose Ph.Eur        93.25                                                   Croscarmellose sodium 4.0                                                     Maize starch paste (5% w/v paste)                                                                   0.75                                                    Magnesium stearate    1.0                                                (d)  Capsule               mg/capsule                                              Compound X            10 mg                                                   Lactose PhEur         488.5                                                   Magnesium stearate    1.5                                                (e)  Injection I           (50 mg/ml)                                              Compound X            5.0% w/v                                                1M Sodium hydroxide solution                                                                        15.0% v/v                                               0.1M Hydrochloric acid                                                        (to adjust pH to 7.6)                                                         Polyethylene glycol 400                                                                             4.5% w/v                                                Water for injection to 100%                                              (f)  Injection II          (10 mg/ml)                                              Compound X            1.0% w/v                                                Sodium phosphate BP   3.6% w/v                                                0.1M Sodium hydroxide solution                                                                      15.0% v/v                                               Water for injection to 100%                                                                         (1 mg/ml,                                          (g)  Injection III         buffered to pH6)                                        Compound X             0.1% w/v                                               Sodium phosphate BP   2.26% w/v                                               Citric acid           0.38% w/v                                               Polyethylene glycol 400                                                                              3.5% w/v                                               Water for injection to 100%                                              (h)  Aerosol I             mg/ml                                                   Compound X            10.0                                                    Sorbitan trioleate    13.5                                                    Trichlorofluoromethane                                                                              910.0                                                   Dichlorodifluoromethane                                                                             490.0                                              (i)  Aerosol II            mg/ml                                                   Compound X            0.2                                                     Sorbitan trioleate    0.27                                                    Trichlorofluoromethane                                                                              70.0                                                    Dichlorodifluoromethane                                                                             280.0                                                   Dichlorotetrafluoroethane                                                                           1094.0                                             (j)  Aerosol III           mg/ml                                                   Compound X            2.5                                                     Sorbitan trioleate    3.38                                                    Trichlorofluoromethane                                                                              67.5                                                    Dichlorodifluoromethane                                                                             1086.0                                                  Dichlorotetrafluoroethane                                                                           191.6                                              (k)  Aerosol IV            mg/ml                                                   Compound X            2.5                                                     Soya lecithin         2.7                                                     Trichlorofluoromethane                                                                              67.5                                                    Dichlorodifluoromethane                                                                             1086.0                                                  Dichlorotetrafluoroethane                                                                           191.6                                              ______________________________________                                    

Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate. The aerosol formulations (h)-(k) may beused in conjunction with standard, metered dose aerosol dispensers, andthe suspending agents sorbitan trioleate and soya lecithin may bereplaced by an alternative suspending agent such as sorbitan monooleate,sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleicacid. ##STR3##

What we claim is :
 1. A heterocyclic cycloalkane of the formula IwhereinQ is pyridyl, or a hydrogenated derivative thereof, which may optionallybear one, two or three substituents selected from halogeno, hydroxy,oxo, carboxy, cyano, amino, (1-4C)alkyl, (1-4C)alkoxy,fluoro-(1-4C)alkyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,hydroxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl,di[(1-4C)alkyl]amino-(1-4C)alkyl, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy andphenyl-(1-4C)alkyl; wherein A is (1-6C)alkylene, (3-6C)alkenylene,(3-6C)alkynylene or cyclo (3-6C)alkylene; wherein X is oxy, thio,sulphinyl, sulphonyl or imino; wherein Ar is phenylene which mayoptionally bear one or two substituents selected from halogeno, hydroxy,amino, nitro, cyano, ureido, carbamoyl, (1-4C)alkyl, (3-4C)alkenyloxy,(1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,fluoro-(1-4C)alkyl, (1-4C)alkoxycarbonyl, N-[(1-4C)alkyl]carbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoylamino, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy and(1-4C)alkoxycarbonyl-(1-4C)alkoxy; wherein R¹ is hydrogen, (1-6C)alkyl,(3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R¹is benzoyl which may optionally bear a substituent selected fromhalogeno, (1-4C)alkyl and (1-4C)alkoxy; and wherein R² and R³ togetherform a (3-6C)alkylene group which, together with the carbon atom towhich R² and R³ are attached, defines a ring having 4 to 7 ring atoms,and which ring may bear one or two substituents, which may be the sameor different, selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl and (1-4C)alkylsulphonyl, or whichring may bear a (1-4C)alkylenedioxy substituent; or apharmaceutically-acceptable salt thereof.
 2. A heterocyclic cycloalkaneof the formula I as claimed in claim 1 wherein Q is pyridyl, or ahydrogenated derivative thereof, which may optionally bear one, two orthree substituents selected from fluoro, chloro, hydroxy, oxo, methyl,ethyl, propyl, trifluoromethyl, 2-fluoromethyl, 2-dimethylaminoethyl andbenzyl;wherein A is methylene, 1-propenylene or 1-propynylene; wherein Xis oxy; wherein Ar is 1,3-phenylene or 1,4-phenylene which mayoptionally bear one or two substituents selected from fluoro, chloro,hydroxy, amino, ureido, methoxy and trifluoromethyl; wherein R¹ ismethyl, ethyl, allyl or 2-propynyl;and wherein R² and R³ together form atetramethylene or pentamethylene group which, together with the carbonatom to which R² and R³ are attached, defines a ring having 5 or 6 ringatoms and which ring may bear a substituent selected from hydroxy,methyl, methoxy and ethoxy; or a pharmaceutically-acceptable saltthereof.
 3. A heterocyclic cycloalkane of the formula I as claimed inclaim 1 wherein Q is 2-pyridyl or 3-pyridyl which may optionally bearone substituent selected from chloro, hydroxy, cyano, methyl, methoxyand trifluoromethyl;A is methylene, ethylene, trimethylene,1-propenylene, 2-methylprop-1-enylene or 1-propynylene; X is oxy; Ar is1,3-phenylene or 1,4-phenylene which may optionally bear one substituentselected from fluoro, chloro, hydroxy, amino, nitro, methyl, methoxy,methylthio, methylsulphinyl, methylsulphonyl, methylamino,dimethylamino, trifluoromethyl, acetamido, cyanomethoxy andcarbamoylmethoxy; R¹ is methyl, ethyl, allyl or 2-propynyl; and R² andR³ together form a tetramethylene or pentamethylene group which,together with the carbon atom to which R² and R³ are attached, defines aring having 5 or 6 ring atoms and which ring may bear a substituentselected from hydroxy, methyl, methoxy, ethoxy, methylthio,methylsulphinyl, methylsulphonyl and methylenedioxy; or apharmaceutically-acceptable salt thereof.
 4. A heterocyclic cycloalkaneof the formula I as claimed in claim 1 wherein Q is 2-pyridyl or3-pyridyl, or a hydrogenated derivative thereof, which may optionallybear one or two substituents selected from hydroxy, oxo, methyl, ethyl,propyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl;wherein A ismethylene, 1-propenylene or 1-propynylene; wherein X is oxy; wherein Aris 1,3-phenylene or 1,4-phenylene which may optionally bear one to twosubstituents selected from fluoro, chloro, amino, methoxy andtrifluoromethyl; wherein R¹ is methyl, ethyl or allyl; and wherein R²and R³ together form a tetramethylene group which, together with thecarbon atom to which R² and R³ are attached, defines a ring having 5ring atoms and which ring may bear a substituent selected from hydroxyand methoxy; or a pharmaceutically-acceptable salt thereof.
 5. Aheterocyclic cycloalkane of the formula I as claimed in claim 1 whereinQ is 2-pyridyl;A is methylene or 1-propynylene; Ar is 1,3-phenylene or5-fluoro-1,3-phenylene; R¹ is methyl; and R² and R³ together form atetramethylene group, which, together with the carbon atom to which R²and R³ are attached, defines a ring having 5 ring atoms and which ringbears a 2-methoxy substituent; or a pharmaceutically-acceptable saltthereof.
 6. A heterocyclic cycloalkane of the formula I, or apharmaceutically-acceptable salt thereof, as claimed in claim 1being:trans-1,2-dimethoxy-1-[3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]cyclopentane.7. A pharmaceutical composition which comprises a heterocycliccycloalkane of the formula I, or a pharmaceutically-acceptable saltthereof, as claimed in any one of claims 1 to 6 in association with apharmaceutically-acceptable diluent or carrier.
 8. A method of treatinga disease or medical condition mediated alone or in part by one or moreleukotrienes which comprises administering to a warm-blooded animalrequiring such treatment an effective amount of a heterocycliccycloalkane of the formula I, or a pharmaceutically-acceptable saltthereof, as claimed in any one of claims 1 to 6.